Hypoglycemia is a critical factor limiting optimal care in type 1 diabetes (T1DM) patients. Recurrent hypoglycemia can lead to hypoglycemia unawareness (HU) by lowering the threshold for activation of glucose sensing mechanisms. HU in turn increases the risk of further hypoglycemic reactions. The commonly recommended goal of improving glycemic control as close to the non-diabetic range as possible increases the likelihood of both recurrent hypoglycemia and HU. However, little is known about the neural pathways underlying the changes in glucose sensing, cortical activity, and cognition associated with recurrent hypoglycemia and hypoglycemia unawareness. The proposed studies will use fMRI in conjunction with the hypoglycemic clamp technique to examine brain activation, cognitive performance, and counterregulatory hormone secretion in three carefully selected groups: 1. T1DM patients with awareness of hypoglycemia (N = 20); 2. T1DM patients with unawareness due to recurrent hypoglycemia (N = 20); and 3. non-diabetic volunteers (N = 20). The primary aim of the proposed research is to build upon our pilot data to carefully delineate both the brain regions involved in counterregulation and the patterns of activation present in T1DM patients and non-diabetic individuals. We will study whether: 1) a hypoglycemic challenge will result in an increase in neural activity in the hypothalamus and will be attenuated in T1DM patients with hypoglycemia unawareness compared to control subjects and T1DM aware patients, 2) activation in regions outside the hypothalamus will be greater in control subjects than in either aware or unaware T1DM patients in response to a hypoglycemic challenge; 3) regional cortical activation in response to cognitive challenge will be reduced during hypoglycemia compared with euglycemia, and whether areas of the brain in T1DM patients that have shown relative gray matter density loss in our previous research will show reduced activation in response to cognitive challenge at both euglycemia and hypoglycemia. This research program will allow us to identify the brain regions involved in glucose sensing as well as the changes in brain activity in patient groups at risk for severe hypoglycemic episodes. With a more precise understanding of these neural processes underlying responses to and regulation of hypoglycemia, approaches to evaluating and developing interventions to address HU can be better designed and developed. [unreadable] [unreadable] [unreadable]